Tumor cell biology and drug resistance
My laboratory has been focusing on understanding of molecular mechanisms of tumorigenesis and tumor drug resistance.
Post-translational modifications play a pivotal role in regulating cellular functions because vast majority of critical proteins, such as transcription factors and nuclear receptors, are subject to such modifications. Small ubiquitin-related modifier (SUMO) conjugations or sumoylation has been recently identified and implicated in regulating a variety of cellular pathways. Like ubiquitination, sumoylation is a multiple step process, involving maturation, activation, conjugation and de-conjugation. As an E2 conjugating enzyme, Ubc9 is essential for sumoylation. Although it is well demonstrated that alterations of ubiquitination pathways can lead to development of cancer, the role for sumoylation in this aspect is unclear. Our recent studies have indicated that Ubc9 plays a role in tumorigenesis. Our long-term goals are to better understand the basis for Ubc9-mediated tumorigenesis and to develop Ubc9-based therapeutic agents for cancer treatment.
MicroRNAs are a class of naturally occurring small non-coding RNAs that control gene expression through the post-transcriptional repression mechanism. To date, over 1,000 human microRNAs have been identified and the number of microRNA is still growing. Aberrant expression of microRNAs has been associated with human disorders, in particular cancer. While some microRNAs function as tumor suppressor, others function as oncogenes. We have recently shown that miR-21 is overexpressed in several types of tumors compared to the matched normal tissues and that more importantly, suppression of miR-21 by a miR-21 inhibitor substantially reduces tumor growth in a xenograft carcinoma mouse model, suggesting that miR-21 is an oncogenic microRNA. On the other hand, miR-145 functions as a tumor suppressor. Of great interest, miR-145 plays a critical role in p53-mediated repression of c-Myc. Finally, we show that microRNAs, such as miR-145 and miR-101, are interconnected with the PI3K/Akt pathway, forming a microRNA-Akt regulatory network. Therefore, characterization of microRNA pathways leading to tumorigenesis will provide new insight into molecular mechanisms underlying microRNA-mediated gene regulation, tumor growth and invasion, and anti-hormone resistance. As a result, this knowledge will aid in the identification of cancer biomarkers and the development of microRNA-based therapeutic agents.
- Sachdeva M, Wu H, Ru P, Hwang L, Trieu V, Mo YY. MicroRNA-101-mediated Akt activation and estrogen-independent growth. Oncogene. 2010 Oct 18. [Epub ahead of print] PubMed PMID: 20956939.
- Gupta A, Mo YY. Detection of microRNAs in cultured cells and paraffin-embedded tissue specimens by in situ hybridization. Methods Mol Biol. 2011;676:73-83.PubMed PMID: 20931391.
- Ng WL, Yan D, Zhang X, Mo YY, Wang Y. Over-expression of miR-100 is responsible for the low-expression of ATM in the human glioma cell line: M059J. DNA Repair (Amst). 2010 Nov 10;9(11):1170-5. PubMed PMID: 20869334; PubMed Central PMCID: PMC2970684.
- Yan D, Ng WL, Zhang X, Wang P, Zhang Z, Mo YY, Mao H, Hao C, Olson JJ, Curran WJ, Wang Y. Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation. PLoS One. 2010 Jul 1;5(7):e11397. PubMed PMID: 20617180; PubMed Central PMCID: PMC2895662.
- Lee J, Padhye A, Sharma A, Song G, Miao J, Mo YY, Wang L, Kemper JK. A pathway involving farnesoid X receptor and small heterodimer partner positively regulates hepatic sirtuin 1 levels via microRNA-34a inhibition. J Biol Chem. 2010 Apr 23;285(17):12604-11. Epub 2010 Feb 25. PubMed PMID: 20185821; PubMed Central PMCID: PMC2857134.
- Sachdeva M, Mo YY. Stroma-mediated expression of estrogen and its role in cancer. Front Biosci. 2010 Jan 1;15:237-48. Review. PubMed PMID: 20036818.
- Zhu S, Sachdeva M, Wu F, Lu Z, Mo YY. Ubc9 promotes breast cell invasion and metastasis in a sumoylation-independent manner. Oncogene. 2010 Mar 25;29(12):1763-72. Epub 2009 Dec 21. PubMed PMID: 20023705; PubMed Central PMCID: PMC2845735.
- Sachdeva M, Mo YY. MicroRNA-145 suppresses cell invasion and metastasis by directly targeting mucin 1. Cancer Res. 2010 Jan 1;70(1):378-87. Epub 2009 Dec 8. PubMed PMID: 19996288; PubMed Central PMCID: PMC2805032.Recommended by Faculty 1000 Medicine. http://f1000.com/2606956# evaluations
- Wu H, Mo YY. Targeting miR-205 in breast cancer. Expert Opin Ther Targets. 2009 Dec;13(12):1439-48. Review. PubMed PMID: 19839716.
- Jiang Q, Feng MG, Mo YY. Systematic validation of predicted microRNAs for cyclin D1. BMC Cancer. 2009 Jun 18;9:194. PubMed PMID: 19538740; PubMed Central PMCID: PMC2728105.
- Huang TH, Wu F, Loeb GB, Hsu R, Heidersbach A, Brincat A, Horiuchi D, Lebbink RJ, Mo YY, Goga A, McManus MT. Up-regulation of miR-21 by HER2/neu signaling promotes cell invasion. J Biol Chem. 2009 Jul 3;284(27):18515-24. Epub 2009 May 6. PubMed PMID: 19419954; PubMed Central PMCID: PMC2709372.
- Ronen O, Malone JP, Kay P, Bivens C, Hall K, Paruchuri LP, Mo YY, Robbins KT, Ran S. Expression of a novel marker, Ubc9, in squamous cell carcinoma of the head and neck. Head Neck. 2009 Jul;31(7):845-55. PubMed PMID: 19309722.
- Sachdeva M, Mo YY. p53 and c-myc: how does the cell balance "yin" and "yang"? Cell Cycle. 2009 May 1;8(9):1303. Epub 2009 May 3. PubMed PMID: 19342882.
- Wu H, Zhu S, Mo YY. Suppression of cell growth and invasion by miR-205 in breast cancer. Cell Res. 2009 Apr;19(4):439-48. PubMed PMID: 19238171; PubMed Central PMCID: PMC2664859. A featured article in 2009. http://www.nature.com/cr/focus/represearch webfocus/index.html
- Wu F, Zhu S, Ding Y, Beck WT, Mo YY. MicroRNA-mediated regulation of Ubc9 expression in cancer cells. Clin Cancer Res. 2009 Mar 1;15(5):1550-7. Epub 2009 Feb 17. PubMed PMID: 19223510; PubMed Central PMCID: PMC2846614.
- Sachdeva M, Zhu S, Wu F, Wu H, Walia V, Kumar S, Elble R, Watabe K, Mo YY. p53 represses c-Myc through induction of the tumor suppressor miR-145. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3207-12. Epub 2009 Feb 6. PubMed PMID: 19202062; PubMed Central PMCID: PMC2651330. 55 citations (Google Scholar); Recommended by Faculty of 1000 Biology. http://f1000.com/1157173#evaluations
- Zhu S, Wu H, Wu F, Nie D, Sheng S, Mo YY. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res. 2008 Mar;18(3):350-9. PubMed PMID: 18270520. 188 citations (Google Scholar); A featured article of 2007-2008.
- Wu F, Chiocca S, Beck WT, Mo YY. Gam1-associated alterations of drug responsiveness through activation of apoptosis. Mol Cancer Ther. 2007 Jun;6(6):1823-30. PubMed PMID: 17575111.
- Zhu S, Si ML, Wu H, Mo YY. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem. 2007 May 11;282(19):14328-36. Epub 2007 Mar 15. PubMed PMID: 17363372. 300 citations (Google Scholar); listed as a hot paper by the Scientist magazine; http://www.the-scientist.com/2009/04/1/61/2/
- Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY. miR-21-mediated tumor growth. Oncogene. 2007 Apr 26;26(19):2799-803. Epub 2006 Oct 30. PubMed PMID: 17072344. 375 citations (Google Scholar).